laboratory investigation

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The subthalamic nucleus (STN) is an important part of the brain related to Parkinson disease (PD) and other involuntary movements. The STN contains

some fibers that travel to the cortical area and basal gan-glia.2 The STN is located just superomedial to the red nucleus and substantia nigra. Widely acknowledged as an important modulator of basal ganglia output, the STN re-ceives its major afferents from the cerebral cortex, thala-mus, globus pallidus externus (GPe), and brainstem. The STN projects mainly to both segments of the GP, sub-stantia nigra, striatum, and brainstem and is essentially composed of glutamatergic neurons. Lesions of the STN induce choreiform abnormal movements and ballism on the contralateral side of the body.2,3 Despite current inter-est, little is known about the relation between function

of the STN and movement. In this study we describe the anatomical relationship between the STN and surrounding structures.

Methodsanatomical study

The cerebral hemispheres and cerebrums of 5 human cadavers were fixed in a 10% formalin solution for at least 3 weeks. The first step in the preparation of the specimens was the removal of the arachnoidal and vascular structures with the aid of a surgical microscope (magnification range ×6 to ×40). The hemispheres were frozen at -16°C for 2–4 weeks. Twenty-four hours after completion of the freezing process, the white fiber dissection was done with fine and

abbreviations DBS = deep brain stimulation; GPe, GPi = globus pallidus externus, globus pallidus internus; PD = Parkinson disease; STN = subthalamic nucleus. subMitted January 16, 2014. accepted October 15, 2014.include when citing Published online April 24, 2015; DOI: 10.3171/2014.10.JNS145.disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Anatomy of the subthalamic nucleus, with correlation of deep brain stimulationAkın Akakın, MD,1 Baran Yılmaz, MD,1 Türker Kılıç, MD,1 PhD, and Albert L. Rhoton Jr., MD2

1Department of Neurosurgery, School of Medicine, Bahcesehir University, Istanbul, Turkey; and 2Department of Neurosurgery, School of Medicine, University of Florida, Gainesville, Florida

obJect The goal in this study was to examine the cadaveric anatomy of the subthalamic nucleus (STN) and to analyze the implications of the findings for deep brain stimulation (DBS) surgery.Methods Five formalin-fixed human cerebrums were dissected using the Klingler fiber dissection technique. Digital photographs of the dissections were fused to obtain an anaglyphic image.results The STN was located posteroinferior to the anterior corticospinal fibers, posterosuperior to the substantia nigra, and anteromedial to the red nucleus, lenticular fasciculus, and thalamic fasciculus. The subthalamic region is ven-tral to the thalamus, medial to the internal capsule, and lateral and caudal to the hypothalamus. The nuclei found within the subthalamic region include the STN. The relationship between the STN and surrounding structures, which are not delineated sharply, is described.conclusions The fiber dissection technique supports the presence of the subthalamic region as an integrative net-work in humans and offers the potential to aid in understanding the impacts of DBS surgery of the STN in patients with Parkinson disease. Further research is needed to define the exact role of the STN in the integrative process.http://thejns.org/doi/abs/10.3171/2014.10.JNS145 Key words neuroanatomy; subthalamic nucleus; fiber dissection; anatomy

» See the corresponding retraction notice, DOI: 10.3171/2015.10.JNS145r, for full details. «

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self-shaped wooden spatulas. We took numerous digital photographs during dissections and, using a specific soft-ware program (Anamaker 3D; available free from www.stereoeye.com), we fused the images to obtain an ana-glyphic image.

resultsanatomical dissection

The dissection of the brain is started from the gray mat-ter of the cortex, and U-fibers are observed under the gray matter. After the removal of U-fibers, the cortical fibers are seen. To expose the superior longitudinal fasciculus, we remove the cortical gray matter; adjacent superficial short fibers of the frontal, temporal, and parietal oper-cula; the middle, frontal, superior, and middle temporal gyri; and the inferior parietal lobule. The first identified fasciculus in dissection, which begins on the lateral hemi-spheric surface, is the superior longitudinal (arcuate) fas-ciculus. Traditionally, this fasciculus can be described as a reversed C-shaped structure, which surrounds the insula and interconnects the frontal and temporal lobes (Fig. 1).

At a deeper level in the temporoparietal area, a group of fibers arching around the posterosuperior insular bor-der is seen to be traveling between the posterior temporal region and the prefrontal area. These fibers form the fron-totemporal or arcuate segment of the superior longitudi-nal fasciculus. By dissecting the inferolateral hemispheric surface, we can see a group of fibers deep to the tempo-roparietal segment of the superior longitudinal fasciculus (Fig. 1).

Progressive dissection of the fibers of the superior lon-gitudinal fasciculus reveals the insular cortex. After re-moval of the insular subcortex, we can see the white fibers of the extreme capsule; and at the level of the limen in-sula, the fibers of the uncinate and inferior occipitofrontal fascicles can be distinguished. The extreme capsule is a group of fibers situated between the insular cortex and the claustrum (Fig. 1).

The external capsule is composed of fibers situated be-

tween the claustrum and the putamen. By removing the fibers of the dorsal extreme capsule, we can see the fibers of the dorsal external capsule at the periphery of the dorsal claustrum. At the level of the limen insula, the uncinate fasciculus and inferior frontooccipital fasciculus can be observed (Fig. 1).

After dissection of the crus cerebri, we first observe the substantia nigra, which is located superolateral to the red nucleus. When the red nucleus is dissected, fibers of the ansa lenticularis can be observed. The STN is located pos-teroinferior to the anterior corticospinal fibers, posterosu-perior to the substantia nigra, and anteromedial to the red nucleus, lenticular fasciculus, and thalamic fasciculus. The STN had a café-au-lait color in cadaver sections (Fig. 2).

Identification of the STNThe STN is a small, lens-shaped nucleus in the brain.

The STN is a part of the basal ganglia system and is lo-cated ventral to the thalamus, dorsal to the substantia nig-ra, and medial to the internal capsule (Fig. 3). Anterior and lateral borders of the STN are enveloped by fibers of the internal capsule, which separates this nucleus laterally from the GP. Posteromedially, the STN is very close to the red nucleus. The ventral borders of the STN are the cerebral peduncle and the substantia nigra. Dorsally, the STN has a border with the fasciculus lenticularis, which separates the STN from the ventral thalamus.

Several fiber tracts course near the borders of the STN. The subthalamic fasciculus consists of fibers that inter-connect the STN and GP. This fiber bundle arises from the inferolateral border of the STN (Fig. 2).

The ansa lenticularis consists of fibers from the globus pallidus internus (GPi) that project toward the thalamus. It originates mainly from the lateral portion of the GPi, coursing in a medial, ventral, and rostral direction and sweeping anteriorly around the posterior limb of the in-ternal capsule. This tract arises from the medial aspect of the GPi, perforates the internal capsule, and forms a bundle ventral to the zona incerta. Although some fibers

FIG. 1. a: Gray matter has been dissected, and fibers have been uncovered. The gyri and sulci have been identified. b: Fibers have been dissected; the claustrum can be seen. Internal capsules have been dissected. The inferior frontal fasciculus and uncinate fasciculus are identified. The optic radiation can be followed inferiorly. c: The claustrum has been dissected, and the putamen is identified. The sagittal stratum can be followed, radiating posteriorly. Fasc. = fasciculus; Front. = frontal; gyr. = gyrus; i.c. = internal capsule; Inf. = inferior; Int. = internal; Lat. Gen. bod = lateral geniculate body; long. = longitudinal; Midd. = middle; Occ. = occipital; rad. = radiation; Sup. = superior; Temp. = temporal. Figure is available in color online only.

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from the lenticular fasciculus are dorsal to the STN, most of this tract courses rostral to the nucleus. Fiber tracts ly-ing posterior to the STN include the medial lemniscus, spinothalamic tract, and trigeminothalamic tract (Fig. 2).

In particular, the dorsal aspects of the lateral portion of the rostral two-thirds and the caudal one-third of the nu-cleus are anatomically related to the motor circuits. Sub-thalamic afferent fibers, corticosubthalamic projections, and most of the cortical afferents to the STN arise from the primary motor cortex, supplementary motor area, pre–supplementary motor area, and premotor area (Fig. 4).

The fibers traveling between the red nucleus and STN are known as the habenular commissure at midline sec-tions of the brain. The mammillary body is located anteri-or to the STN. The mammillothalamic pathway is located anterosuperior to the STN (Fig. 4).

Atlas-Based Localization of the Subthalamic RegionUsing the 3 spatial MRI planes and applying the ana-

tomical knowledge acquired from the cadaveric dissec-tions, we can localize the subthalamic region. This region is located ventral to the thalamus, medial to the internal capsule, and lateral and caudal to the hypothalamus. The

nuclei found within the subthalamic region include the STN and zona incerta. The STN has a very close relation-ship with the substantia nigra and the red nucleus (Fig. 5).

discussionThe STN is a small, lens-shaped nucleus in the brain.

The STN is part of the basal ganglia system and is located ventral to the thalamus, dorsal to the substantia nigra, and medial to the internal capsule. It was first described by Jules Bernard Luys in 1865, and the terms corpus luysi and Luys body are still sometimes used. The STN is sur-rounded by dense bundles of myelinated fibers.2 Dorsally the STN is bordered by a portion of the fasciculus len-ticularis and the zona incerta, which separate this nucleus from the ventral thalamus.2–7,10,12 As a consequence, the STN does not have sharp borders with the surrounding structures. Hence, the dissection is very difficult in this intricate region because of the challenge involved in cal-culating any anatomical measurement.

The volume of the STN is 40 mm3 in humans. The rela-tionship between the volume of the STN and the total vol-ume of the brain is proportionally similar in all humans.6

FIG. 2. Left: View from the medial aspect of the cerebrum. The red nucleus can be viewed medial to the substantia nigra. The thalamus is located posterolateral to the substantia nigra. The optic nerve and the stalk can be observed medially. right: Subtha-lamic nucleus and ansa lenticularis fibers are seen. Association fibers between basal ganglia and the STN can be viewed. The red nucleus is located medially and inferiorly. The ansa lenticularis and substantia nigra can be seen on the inferior and lateral side of the STN, respectively. Pit. = pituitary. Figure is available in color online only.

FIG. 3. Left: Cortical fibers, GPi, and GPe have been dissected. The STN, substantia nigra, and crus cerebri are displayed, and the thalamus can also be seen. right: White matter has been completely dissected. The STN can be seen inferior to the red nucleus. The substantia nigra and red nucleus can be observed. The optic nerve has been sectioned. Figure is available in color online only.

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Chronic stimulation of the STN, called deep brain stimulation (DBS), is used to treat patients with PD. The first cells to be stimulated are the terminal arborizations of afferent axons; the stimulation modifies the activity of subthalamic neurons.11

The function of the STN is unknown, but current theo-ries present it as a component of the basal ganglia control system, which may perform action selection. Dysfunction of the STN has also been shown to increase impulsivity in individuals presented with two equally rewarding stimuli. The STN is populated mainly by projection neurons.

The first intracellular electrical recordings of subtha-lamic neurons were performed using sharp electrodes in a rat slice preparation.1 Several recent studies have focused on the autonomous pace-making ability of the subthalam-ic neurons. These neurons are often referred to as “fast-spiking pacemakers.”

The connection of the lateral pallidum with the STN is part of the basal ganglia. The activity of the medial pal-lidum is influenced by afferent signals from the lateral pallidum and the STN. The STN sends axons to anoth-er regulator region: the pedunculopontine complex. The lateropallido-subthalamic system is thought to have a key

FIG. 4. Lateral appearance of the anterior commissure posteriorly and dentate rubrothalamic tract anteriorly. a: The STN is inferior to the crus cerebri. The substantia nigra and the red nucleus can be seen at the anterior part of the corticospinal tract fibers. b: The midbrain, pons, and cerebellum have been dissected. The substantia nigra and the red nucleus are clearly visible. The superior and inferior colliculus are posterior to the STN. The superior cerebellar peduncle is lateral to the substantia nigra and inferolateral to the STN. c: The STN, the primary motor cortex, and the premotor cortex are shown, which illustrates the relationship between these structures in a wide anatomical dissection. The optic nerve has been cut so that the lateral geniculate body can be seen. d: Medial appearance of the cerebrum. The mammillothalamic tract and the STN can be seen close to the thalamus. The habenular commissure, which includes the posterior commissure and the habenular nucleus, can be observed. Subthalamic-cortical fibers can be followed. Ant = anterior; cer. Ped. = cerebellar peduncle. Figure is available in color online only.

FIG. 5. Three spatial MRI planes and atlas-based localization of the subthalamic region. Figure is available in color online only.

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role in the generation of the patterns of activity seen in PD.9

In clinical practice, DBS of the STN is a promising new surgical option for the treatment of advanced PD. The marked clinical benefits obtained in these severely disabled patients outweigh the adverse effects.4 Accurate positioning of the electrodes allows the effects of stimula-tion to be confined to sensorimotor circuits.8

conclusionsThe fiber dissection technique supports the presence of

the subthalamic region as an integrative network in hu-mans and offers the potential to aid in understanding the impacts of DBS surgery of the STN in patients with PD. Further research is needed to delineate definitively the role of the STN in the integrative process. Fiber dissec-tions, done in conjunction with electrophysiological visu-alization or other techniques, offer confirmatory evidence that can lead to improvements in atlas-based localization of the subthalamic region.

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12. Sarma SV, Eden UT, Cheng ML, Williams ZM, Hu R, Es-kandar E, et al: Using point process models to compare neu-ral spiking activity in the subthalamic nucleus of Parkinson’s patients and a healthy primate. IEEE Trans Biomed Eng 57:1297–1305, 2010

Author ContributionsConception and design: Akakın, Rhoton. Acquisition of data: Yıl-maz, Rhoton. Analysis and interpretation of data: Kılıç, Rhoton.

correspondenceAkın Akakın, Department of Neurosurgery, Bahcesehir Univer-sity School of Medicine, Cıragan Caddesi Osmanpasa Mektebi Sokak No: 4-6, 34353 Besiktas, Istanbul 81156, Turkey. email: drakinakakin@yahoo.com.

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